Increasing evidence suggests that TRH functions as a neuromodulator of alpha motoneurons and that exogenous TRH may reduce the motor deficit of spinal cord injury and motor neuron disease. Since TRH crosses the blood brain barrier poorly, and parenteral administration results in, at best, modest motor improvement accompanied by considerable toxicity, we have explored its intrathecal (IT) administration in patients with ALS. Our preliminary studies have shown that IT TRH is safe and well tolerated. Our pharmacodynamic studies reveal that IT TRH has a much longer half-life in CSF (54 min.) than in blood (3-5 min.) and that only small amounts escape the CSF/CNS compartment (2.75% in 2 hrs). We have recently completed an open label controlled study of IT TRH given by implanted pump at a constant infusion rate of 3mg/dy for 6 months in three patients. We achieved in CSF steady-state TRH level comparable to that shown to have a trophic effect on motoneurons in tissue culture (.1mM). Deterioration was measured by a unique quantitative technique. The patients receiving IT constant infusion were compared to four control groups: 1) the patients themselves prior to starting TRH; 2) three patients receiving IT TRH by individual lumbar puncture 500mcg twice weekly; 3) two patients receiving TRH 150mg subcutaneously twice weekly, and 4) 41 patients followed for 12 or more months received no specific therapy. In each instance, the group receiving TRH by IT constant infusion deteriorated at a slower rate. The course of deterioration in arms and legs was slowed by more than 50%. In view of these encouraging pilot data, we propose to carry out a controlled, blinded, parallel, crossover study in 30 patients. The course of deterioration will be measured by both the TQNE and quantitative neurophysiologic techniques. We believe this experiment will answer the growing controversy about the therapeutic efficacy of TRH. Simultaneously, we will study the metabolic, endocrine and behavioral effects of chronic TRH administration.